Which patient populations are often missing from clinical trials of newer agents for type 2 diabetes mellitus (T2DM) management in older adults?

Patients Older Than 80 Years Living in Institutional Settings Are Missing from Clinical Trials of Newer Agents for T2DM

Patients who are older than 80 years and living somewhere other than at home are the population most consistently missing from clinical trials of newer agents for type 2 diabetes mellitus management in older adults. 1

Evidence Analysis

The 2024 American Diabetes Association (ADA) Standards of Care highlights significant gaps in clinical trial representation for very elderly patients with diabetes, particularly those in institutional settings 1. While the ADA guidelines identify three major classes of older patients with diabetes (healthy, geriatric, and cardiovascular), they note that patients with significant functional impairment or those in institutional settings are often excluded from major clinical trials.

The systematic review and network meta-analysis conducted by the American College of Physicians (2024) further supports this conclusion 1. This comprehensive analysis of 84 trials examining newer diabetes medications (SGLT2 inhibitors, GLP-1 agonists, DPP-4 inhibitors, and long-acting insulins) revealed that:

• The mean age of participants was only 58.7 years
• Most studies enrolled middle-aged adults with long-standing T2DM (mean duration 8.8 years)
• Trials predominantly included ambulatory patients capable of participating in complex study protocols
• Institutional settings and very elderly populations (>80 years) were notably absent

Why This Matters for Clinical Outcomes

The exclusion of very elderly institutionalized patients has significant implications for morbidity and mortality outcomes:

1. Hypoglycemia risk: Elderly institutionalized patients are at particularly high risk for hypoglycemia, which can lead to falls, cognitive impairment, and increased mortality 1

2. Medication safety: The pharmacokinetics and pharmacodynamics of diabetes medications change with advanced age, especially in those with multiple comorbidities and polypharmacy common in institutional settings 2

3. Functional outcomes: Treatment goals for very elderly institutionalized patients often prioritize quality of life and functional status over strict glycemic control 1

Examining the Other Patient Populations

Let's examine why the other patient populations mentioned in the question are better represented in clinical trials:

1. Patients living at home with chronic kidney disease: Multiple trials have specifically included patients with CKD. The ACP review identified three trials that required participants to have CKD 1.

2. Patients with heart failure and cardiovascular disease: These patients are well-represented in contemporary trials. The ACP review noted that four trials required participants to have existing CVD or acute coronary syndrome, and eleven required them to be "at risk for cardiovascular disease" 1. Additionally, GLP-1 agonists and SGLT2 inhibitors have been extensively studied in patients with established cardiovascular disease 3.

3. Patients who are 65 years old with proteinuria: While elderly patients are underrepresented, those at age 65 with proteinuria would likely be captured in the CKD-focused trials mentioned above. The ADA guidelines specifically mention that the presence of albuminuria (30-299 mg/day) is associated with increased risk of CVD and CKD in T1DM and T2DM, indicating this population has been studied 1.

Clinical Implications

For clinicians managing very elderly institutionalized patients with T2DM, this evidence gap means:

• Treatment decisions must be made with limited direct evidence for this population
• Goals of care should focus on avoiding hypoglycemia and symptomatic hyperglycemia while reducing treatment burden 1
• Medication selection should prioritize agents with low hypoglycemia risk and minimal side effects
• Individualized A1C targets should be less stringent than for younger, healthier patients

One small case series examining T2DM management in patients aged 80+ (mean age 88.1, range 80-104) found that GLP-1 receptor agonists were well-tolerated and effective, allowing reduction in hypoglycemia-inducing agents like sulfonylureas and insulin 2. However, this study primarily included community-dwelling elderly rather than those in institutional settings.

In conclusion, while clinical trials have made progress in including patients with comorbidities like CKD and cardiovascular disease, there remains a significant evidence gap for very elderly patients (>80 years) living in institutional settings, making this the patient population most consistently missing from clinical trials of newer agents for T2DM management.